Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer McDermott, et al. Oncotarget. 2017
| Autor: | John Crown |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CA15-3 Chromatin Immunoprecipitation Transcription Genetic medicine.drug_class Blotting Western Estrogen receptor Anti estrogen Antineoplastic Agents Breast Neoplasms News Polymerase Chain Reaction Mice 03 medical and health sciences breast cancer Breast cancer Cell Line Tumor Animals Humans Medicine Receptor Fulvestrant Protein Kinase Inhibitors Oligonucleotide Array Sequence Analysis Estradiol business.industry Estrogen Receptor alpha anti-estrogens Estrogens Cyclin-Dependent Kinase 8 medicine.disease Xenograft Model Antitumor Assays CDK-8 030104 developmental biology Oncology Drug Resistance Neoplasm Estrogen CDK19 Cancer research Cyclin-dependent kinase 8 Female Transcriptome business estrogen receptor |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.15354 |
| Popis: | Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERα expression, suggesting that CDK8 could be functionally associated with ER. We have found that CDK8 inhibition by CDK8/19-selective small-molecule kinase inhibitors, by shRNA knockdown or by CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells; this effect was exerted downstream of ER. Estrogen addition stimulated the binding of CDK8 to the ER-responsive GREB1 gene promoter and CDK8/19 inhibition reduced estrogen-stimulated association of an elongation-competent phosphorylated form of RNA Polymerase II with GREB1. CDK8/19 inhibitors abrogated the mitogenic effect of estrogen on ER-positive cells and potentiated the growth-inhibitory effects of ER antagonist fulvestrant. Treatment of estrogen-deprived ER-positive breast cancer cells with CDK8/19 inhibitors strongly impeded the development of estrogen independence. In vivo treatment with a CDK8/19 inhibitor Senexin B suppressed tumor growth and augmented the effects of fulvestrant in ER-positive breast cancer xenografts. These results identify CDK8 as a novel downstream mediator of ER and suggest the utility of CDK8 inhibitors for ER-positive breast cancer therapy. |
| Databáze: | OpenAIRE |
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